Approximately 2 percent of the U.S. population has HCV antibodies, and it is estimated that 10,000 people die annually of HCV-related complications including liver failure or cancer. Although new therapies have improved the rates of sustained response, the majority of patients are nonresponders to antiviral treatment, remaining at risk for disease progression. Although chronic HCV infection is very common, it is rarely identified acutely, and patients rarely seek medical attention until long after chronic infection is established. The very nature of this infection has made it extraordinarily difficult to study the early disease course except in the subset of individuals with definitive early symptoms and diagnosis. In this proposal we will direct our studies to the analyses of the specific cellular immune response to hepatitis C virus (HCV) infection as it occurs very early following acute infection in a community-based cohort we have identified. The recent development of immunologic techniques that directly quantitate virus-specific lymphocytes ex-vivo will enable us to study the interactive mechanisms among virus, clinical disease, and host immune responses from the incubation phase. Detailed information of this stage of infection is clearly of value both in understanding the pathogenesis of the disease and potentially vaccine design. Our goal is to elucidate the cellular immune and virologic events in the initial stages of HCV infection that are likely to be crucial in determining self-limited infection versus chronic viral persistence and progressive liver injury. The specific aims outlined in this proposal include: To precisely examine the magnitude, kinetics, and breadth of HLA class I- and II- restricted cellular immune responses directed specifically against HCV and assess how these responses correlate with recovery versus chronic evolution; to characterize the temporal relationships between the level of HCV replication, its genetic diversity and the subsequent cellular immune response elicited by the viral infection. We propose to define how the host immune response shapes the kinetics of HCV replication. Furthermore, we anticipate that a subset of individuals who initially showed vigorous CD8+ T cell responses and control of viral replication will demonstrate abrogated HCV-specific immune responses over time and this will be associated with a rebound in circulating HCV viremia. In this subset of individuals, we propose to examine whether viral mutational events (yielding a high ratio of amino acid-changing substitutions to antigenically silent nucleotide base changes) in CD8+ T cell epitopes in viva has led to the generation of variant peptides that are no longer recognized by T cells.